Dendrophanes: Water‐soluble dendritic receptors as models for buried recognition sites in globular proteins

Abstract

Water-soluble dendritic cyclophanes (dendrophanes) of first (1, 4), second (2, 5), and third generation (3, 6) with poly(ether amide) branching and 12, 36, and 108 terminal carboxylate groups, respectively, were prepared by divergent synthesis, and their molecular recognition properties in aqueous solutions were investigated. Dendrophanes 1-3 incorporate as the initiator core a tetraoxa[6.1.6.l]paracyclophane 7 with a suitably sized cavity for inclusion compiexation of benzene or naphthalene derivatives. The initiator core in 4-6 is the [6.1.6.l]cyclophane 8 shaped by two naphthyl(pheny1)methane units with a cavity suitable for steroid incorporation. The syntheses of 1-6 involved sequential peptide coupling to monomer 9, followed by ester hydrolysis (Schemes 1 and 4).Purification by gel-permeation chromatography (GPC; Fig. 3) and full spectral characterization were accomplished at the stage of the intermediate poly(methy1 carboxylates) 10-12 and 23-25, respectively. The third-generation 108-ester 25 was also independently prepared by a semi-convergent synthetic strategy, starting from 4 (Scheme 5). All dendrophanes with terminal ester groups were obtained in pure form according to the I3C-NMR spectral criterion (Figs. 1 and 5). The MALDI-TOF mass spectra of the third-generation derivative 25 (mol. wt. 19328 D) displayed the molecular ion as base peak, accompanied by a series of ions [M -n(1041 7)]+, tentatively assigned as characteristic fragment ions of the poly(ether amide) cascade. A similar fragmentation pattern was also observed in the spectra of other higher-generation poly(ether amide) dendrimers. Attempts to prepare monodisperse fourth-generation dendrophanes by divergent synthesis failed. 'H-NMR and fluorescence binding titrations in basic aqueous buffer solutions showed that dendrophanes 1-3 complexed benzene and naphthalene derivatives, whereas 4-6 bound the steroid testosterone. Complexation occurred exclusively at the cavity-binding site of the central cyclophane core rather than in fluctuating voids in the dendritic branches, and the association strength was similar to that of the complexes formed by the initiator cores 7 and 8, respectively (Tables f and 3). Fluorescence titrations with 6-(p-tolnidino)naphthalene-2-sulfonate as fluorescent probe in aqueous buffer showed that the micropolarity at the cyclophane core in dendrophanes 1-3 becomes increasingly reduced with increasing size and density of the dendritic superstructure; the polarity at the core of the third-generation compound 3 is similar to that of EtOH (Table 2). Host-guest exchange kinetics were remarkably fast and, except for receptor 3, the stabilities of all dendrophane complexes could be evaluated by 'H-NMR titrations. The rapid complexation-decomplexation kinetics are explained by the specific attachment of the dendritic wedges to large, nanometer-sized cyclophane initiator cores, which generates apertures in the surrounding dendritic superstructure.

Dendritic encapsulation of active core molecules

“…Alternatively, the central core of the dendrimer can be a cyclophane with welldefined complexation ability. Diederich et al have described examples of such dendritic host molecules they called dendrophanes [31][32][33]. The recognition site is, at least to some extent, shielded from its medium, implying a typical nano-environment inside the dendrimer and such structures can serve as models for globular proteins.…”

Supramolecular Solubilisation of Hydrophilic Dyes by Using Individual Dendritic Branches

“…[4,12] Particularly noteworthy in this context are the reports of Diederich and coworkers, illustrating that a dendritic cyclophane (dendrophane) generates a unique environment at its selective encapsulated binding site, a feature which was probed by using the l max value of 6-(p-toluidino)naphthalene-2-sulfonate (TNS), which is a fluorescent probe of the dendritic microenvironment. [13] In 1999, Twyman and co-workers reported a water-soluble, polar spherical dendrimer possessing interior amine groups that was capable of solubilising organic acids (such as benzoic acid) in aqueous solution. [14] It was argued that specific carboxylic acid ± amine interactions played a key role in the solubilisation process.…”

Supramolecular chemistry of dendrimers with functional cores

“…1) with poly(ether amide) branching and 12, 36, and 108 terminal carboxyl groups, respectively, were prepared as the first water-soluble dendrimers with a defined active recognition site at the central core (21)(22)(23). Whereas series 1-3 features a central cyclophane core with a binding cavity complementary in size to benzene and naphthalene guests, the second series 4-6 was designed to complex large steroidal substrates.…”